The non-muscle-myosin-II heavy chain Myh9 mediates colitis-induced epithelium injury by restricting Lgr5+ stem cells

Nat Commun. 2015 May 13;6:7166. doi: 10.1038/ncomms8166.

Abstract

Lgr5+ stem cells are crucial to gut epithelium homeostasis, and therapies targeting these cells hold promise for treatment of gastrointestinal diseases. Here we report that the non-muscle-myosin-II (NMII) heavy chain Myh9 accumulates at epithelial injury sites in mice distal colon treated with dextran sulphate sodium (DSS). Gut-epithelium-specific Myh9 monoallelic deletion alleviates DSS-induced colonic crypt damage and acute colitis. Consistently, the NMII inhibitor blebbistatin can improve the survival of Lgr5+ stem cells and the growth of Lgr5 organoids. Mechanistically, inhibition of NMII by blebbistatin or Myh9 monoallelic deletion activates Akt through Rac1 and PAK1, which is essential for the survival and pluripotency of Lgr5+ cells. These results establish a critical role of the Myh9-Rac1-PAK1-Akt pathway in the maintenance of Lgr5+ stem cells. As blebbistatin can mitigate DSS-induced colitis and preserve Lgr5+ colonic stem cells in vivo, our findings provide a potential therapeutic intervention of gastrointestinal epithelium injury and degenerative diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Aminoquinolines / chemistry
  • Animals
  • Cell Survival
  • Colitis / metabolism
  • Colitis / pathology*
  • Epithelium / pathology*
  • Gene Expression Regulation*
  • Green Fluorescent Proteins / metabolism
  • Heterocyclic Compounds, 4 or More Rings / chemistry
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / pathology
  • Male
  • Mice
  • Myosin Type II / metabolism*
  • NIH 3T3 Cells
  • Neuropeptides / metabolism
  • Nonmuscle Myosin Type IIA / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyrimidines / chemistry
  • Receptors, G-Protein-Coupled / metabolism
  • Signal Transduction
  • Stem Cells / cytology*
  • p21-Activated Kinases / metabolism
  • rac1 GTP-Binding Protein / metabolism

Substances

  • Aminoquinolines
  • Heterocyclic Compounds, 4 or More Rings
  • Lgr5 protein, mouse
  • Myh9 protein, mouse
  • NSC 23766
  • Neuropeptides
  • Pyrimidines
  • Rac1 protein, mouse
  • Receptors, G-Protein-Coupled
  • Green Fluorescent Proteins
  • blebbistatin
  • Pak1 protein, mouse
  • Proto-Oncogene Proteins c-akt
  • p21-Activated Kinases
  • Myosin Type II
  • Nonmuscle Myosin Type IIA
  • rac1 GTP-Binding Protein